Role of Hydrophobicity and Solvent-Mediated Charge-Charge Interactions in Stabilizing α-Helices

Vila, Jorge A.; Ripoll, Daniel R.; Villegas, Mercedes; Vorobjev, Yury N.; Scheraga, Harold A.

doi:10.1016/s0006-3495(98)77709-4

Cited by 36 publications

(44 citation statements)

References 65 publications

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“…as well as entropic contributions (the difference between the Ala and Gly propensities can be explained by a large reduction in conformational space available when the side-chain H of a glycine is replaced by a CH3 in Ala) (54)(55)(56)(57)(58). Many of these effects can be accounted for by a semiempirical free energy of solvation (59).…”

Section: Resultsmentioning

confidence: 99%

Structure-based conformational preferences of amino acids

Koehl

Levitt

1999

Proc. Natl. Acad. Sci. U.S.A.

137

118

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Proteins can be very tolerant to amino acid substitution, even within their core. Understanding the factors responsible for this behavior is of critical importance for protein engineering and design. Mutations in proteins have been quantified in terms of the changes in stability they induce. For example, guest residues in specific secondary structures have been used as probes of conformational preferences of amino acids, yielding propensity scales. Predicting these amino acid propensities would be a good test of any new potential energy functions used to mimic protein stability. We have recently developed a protein design procedure that optimizes whole sequences for a given target conformation based on the knowledge of the template backbone and on a semiempirical potential energy function. This energy function is purely physical, including steric interactions based on a Lennard-Jones potential, electrostatics based on a Coulomb potential, and hydrophobicity in the form of an environment free energy based on accessible surface area and interatomic contact areas. Sequences designed by this procedure for 10 different proteins were analyzed to extract conformational preferences for amino acids. The resulting structure-based propensity scales show significant agreements with experimental propensity scale values, both for ␣-helices and ␤-sheets. These results indicate that amino acid conformational preferences are a natural consequence of the potential energy we use. This confirms the accuracy of our potential and indicates that such preferences should not be added as a design criterion. P redicting protein structure requires an understanding of how tertiary structure depends on the primary amino acid sequence. An intuitive approach to that problem is to explore the wealth of information in experimental structures solved at atomic resolution and stored in protein databanks such as the PDB (1). It is observed that the three-dimensional structure of a protein is hierarchical, with a local organization of the amino acids into secondary structure elements (␣-helices and ␤-sheets), which are themselves organized in space to form the tertiary structure. The same hierarchy is used in most ab initio protein structure prediction protocols. Secondary structures are predicted first, usually based on statistical analysis of known protein structures and multiple sequence alignments. Then various close-packing arrangements of these helices and strands are tested, either systematically or by deterministic optimization tools [for a recent review, see Koehl and Levitt (2)]. It is therefore important to understand the physical basis for the correlation between sequence and the presence of an ␣-helix or a ␤-sheet in the structure. In this paper, we derive structure-based secondary-structure propensity scales for amino acids, using a physical all-atom potential energy function.Statistical surveys of proteins of known structures (3-7) revealed that amino acids have clear conformational preferences for one type of secondary structure. The ...

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Section: Resultsmentioning

confidence: 99%

Structure-based conformational preferences of amino acids

Koehl

Levitt

1999

Proc. Natl. Acad. Sci. U.S.A.

137

118

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“…This is also observed in experiments on many heterogeneous peptides that can be folded into alternative stable structures by changing the solution conditions such as the pH, salt, or organic cosolvent concentration; peptide concentration; and the redox state (Rosenheck and Doty 1961;Kabsch and Sander 1984;Mutter and Hersperger 1990;Mutter et al 1991;Reed and Kinzel 1991;Zhong and Johnson 1992;Cohen et al 1993;Dado and Gellman 1993;Waterhous and Johnson 1994;Cerpa et al 1996;Fukushima 1996;Schenck et al 1996;Zhang and Rich 1997;Tuchscherer et al 1999;Awasthi et al 2001;Wildman et al 2002). Although there are many computer simulation studies in which the transition between ␣-helix and random coil of polyalanines is observed (Okamoto and Hansmann 1995;Vila et al 1998;Hansmann and Okamoto 1999;Alves and Hansmann 2000;Mitsutake and Okamoto 2000;Alves and Hansmann 2001;Garcia and Sanbonmatsu 2002;Olivella et al 2002;Peng and Hansmann 2002;Ghosh et al 2003;Ohkubo and Brooks III 2003;Peng et al 2003), there are only two studies thus far that predict the formation of both ␣-helix and ␤-structures (Levy et al 2001;Ding et al 2003). The vast majority of simulation studies by other investigators mentioned here are based on all-atom models, which prevents them from exploring transitions between different peptide structures over a wide range of solvent conditions and temperatures.…”

Section: Discussionmentioning

confidence: 99%

Solvent effects on the conformational transition of a model polyalanine peptide

2004

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We have investigated the folding of polyalanine by combining discontinuous molecular dynamics simulation with our newly developed off-lattice intermediate-resolution protein model. The thermodynamics of a system containing a single Ac-KA 14 K-NH 2 molecule has been explored by using the replica exchange simulation method to map out the conformational transitions as a function of temperature. We have also explored the influence of solvent type on the folding process by varying the relative strength of the side-chain's hydrophobic interactions and backbone hydrogen bonding interactions. The peptide in our simulations tends to mimic real polyalanine in that it can exist in three distinct structural states: ␣-helix, ␤-structures (including ␤-hairpin and ␤-sheet-like structures), and random coil, depending upon the solvent conditions. At low values of the hydrophobic interaction strength between nonpolar side-chains, the polyalanine peptide undergoes a relatively sharp transition between an ␣-helical conformation at low temperatures and a random-coil conformation at high temperatures. As the hydrophobic interaction strength increases, this transition shifts to higher temperatures. Increasing the hydrophobic interaction strength even further induces a second transition to a ␤-hairpin, resulting in an ␣-helical conformation at low temperatures, a ␤-hairpin at intermediate temperatures, and a random coil at high temperatures. At very high values of the hydrophobic interaction strength, polyalanines become ␤-hairpins and ␤-sheet-like structures at low temperatures and random coils at high temperatures. This study of the folding of a single polyalanine-based peptide sets the stage for a study of polyalanine aggregation in a forthcoming paper.Keywords: polyalanine; ␣-␤ transition; secondary structures; solvent conditions; discontinuous molecular dynamics Small peptides undergo a spontaneous reversible disorderto-order transition to a unique, three-dimensional equilibrium structure such as an ␣-helix or a ␤-structure when exposed to favorable physiological conditions. The information necessary to drive this folding transition is universally accepted to be encrypted solely within the linear amino acid sequence (Anfinsen 1973;Anfinsen and Scheraga 1975). However, experiments indicate that many peptides can be folded into alternative stable structures by changing the solution conditions (Rosenheck and Doty 1961;Kabsch and Sander 1984;Mutter and Hersperger 1990;Mutter et al. 1991;Zhong and Johnson 1992;Cohen et al. 1993;Waterhous and Johnson 1994). For example, many peptides are well known to undergo a sharp helix-coil transition as the temperature is increased (Poland and Scheraga 1970;Rohl and Baldwin 1998). Furthermore, the conformational transition between the ␣-helix and ␤-structure is greatly influenced by solvent conditions, including the pH (Mutter and Hersperger 1990;Cerpa et al. 1996;Tuchscherer et al. 1999), the temperature (Cerpa et al. 1996;Fukushima 1996;Zhang and Rich 1997), the salt or organic cosolvent ...

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“…At low PS-20/ darbepoetin alfa (<1.5), the binding may only cause hydration changes to local regions of the protein, increasing the observed relative helicity. [63][64][65][66][67] As the PS-20/darbepoetin alfa (>1.5) increases, PS-20 binding could start to partially unfold the protein, causing the Trp to become more hydrated (lower quantum yield) and causing the decrease in relative helicity. In contrast, PS-80 binds to protein without unfolding the protein over a broader range of PS-80/darbepoetin alfa.…”

Section: Discussionmentioning

confidence: 99%